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J. Org. Chem. 2001, 66, 7394-7401
Energy Barriers to Rotation in Axially Chiral Analogues of 4-(Dimethylamino)pyridine Alan C. Spivey,*,† Patrick Charbonneau,‡ Tomasz Fekner,†,§ Detlev H. Hochmuth,| Adrian Maddaford,† Cecile Malardier-Jugroot,‡ Alison J. Redgrave,⊥ and Michael A. Whitehead‡ Department of Chemistry, University of Sheffield, Brook Hill, Sheffield S3 7HF, U.K., Theoretical Chemistry Laboratory, Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, Quebec, Canada H3A 2K6, Institut fu¨ r Organische Chemie, Universita¨ t Hamburg, Martin-Luther-King-Platz 6, 20146 Hamburg, Germany, and GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
[email protected] Received February 26, 2001
The barriers to enantiomerization of a series of axially chiral biaryl analogues of 4-(dimethylamino)pyridine (DMAP) 1-10 were determined experimentally by means of dynamic HPLC measurements and racemization studies. The barriers to rotation in derivatives 1-6 (based on the bicyclic 5-azaindoline core) were lower than those in the corresponding derivatives 7-10 (based on the monocyclic DMAP core). Semiempirical (PM3), ab initio Hartree-Fock (HF/STO-3G), and density functional theory (DFT/B3LYP/6-31G*) calculations reveal that these differences in barriers to rotation are the result of differing degrees of hybridization of the non-pyridyl nitrogen in the enantiomerization transition states (TSs). The importance of heteroatom hybridization as a factor in determining nonsteric contributions to barriers to rotation in azabiaryls of this type is discussed. Introduction We have recently described the synthesis of a novel series of axially chiral biaryl analogues (II and III) of the highly nucleophilic acylation catalyst 4-(dimethylamino)pyridine (DMAP) I. We have also shown that certain analogues, having sufficiently high barriers to rotation about the biaryl axis for their atropisomers to be configurationally stable, can be used in an enantiomerically pure form as catalysts for the efficient kinetic resolution of secondary alcohols.2-5 During the development of these chiral catalysts, our initial studies focused on 7-aryl derivatives of 1-methyl-2-pyrrolino[3,2-c]pyridine (N-methyl-5-azaindoline) II as we anticipated that this bicyclic core unit would impart a higher resistance * To whom correspondence should be addressed. Tel: +44(0)114 2229467. Fax: +44(0)114 27-38673. E-mail:
[email protected]. † University of Sheffield. ‡ McGill University. § Present address: Department of Chemistry, The Ohio State University, 100 West 18th Ave., Columbus, OH 43210. | Universita ¨ t Hamburg. ⊥ GlaxoSmithKline Medicines Research Centre. (1) Enantiomerization refers to the reversible microscopic interconversion of enantiomers with a rate constant kenant. Racemization refers to the irreversible macroscopic conversion of an optically active mixture of enantiomers into or toward the racemate with a rate constant kracem where kracem ) 2kenant since the interconversion of one molecule reduces the enantiomeric excess (ee) by two molecules. Dynamic HPLC studies and PM3, HF/STO-3G, and DFT/B3LYP/6-31G* calculations give kenant directly, whereas Eyring plots give kracem directly. Consequently, a statistical correction factor of 0.5 has been applied to the Eyring rate data to obtain correct kinetic parameters for enantiomerization (see Supporting Information). (2) Spivey, A. C.; Fekner, T.; Adams, H. Tetrahedron Lett. 1998, 39, 8919-8922. (3) Spivey, A. C.; Fekner, T.; Spey, S. E.; Adams, H. J. Org. Chem. 1999, 64, 9430-9443. (4) Spivey, A. C.; Fekner, T.; Spey, S. E. J. Org. Chem. 2000, 65, 3154-3159. (5) Spivey, A. C.; Maddaford, A.; Redgrave, A. Org. Prep. Proced. Int. 2000, 32, 331-365.
to rotation about the biaryl axis relative to the DMAP6 core in analogous 3-aryl-DMAP derivatives III.3 However, this turned out not to be the case: at ambient temperature, the 3-aryl-DMAP derivatives exhibit higher barriers to biaryl rotation than the corresponding N-methyl5-azaindoline derivatives.3,7 Here, we correlate the experimentally determined rotational barriers obtained by computer simulation of dynamic enantioselective HPLC chromatograms and from Eyring plots of racemization data with theoretical rotational barriers obtained by semiempirical (PM3), ab initio Hartree-Fock (HF/ STO-3G), and density functional theory (DFT/B3LYP/631G*) methods for both series. Analysis of the data allows rationalization of the experimentally determined rotational barriers and prediction of barriers for compounds for which experimental data could not be obtained.
Results and Discussion The experimentally determined barriers to rotation (∆G#) about the biaryl axis of DMAP derivatives 1-10 are shown in Figure 1. The barriers for configurationally labile derivatives 1-3, 7, and 88 were determined by computer simulation of dynamic enantioselective HPLC (6) The acronym DMAP is used here for all monocyclic 4-(dialkylamino)pyridine-based structures, not just 4-(dimethylamino)pyridine. (7) In an enantiomerically pure form, DMAP derivatives also impart significantly higher levels of stereoinduction in KR experiments than their N-methyl-5-azaindoline analogues (see ref 4).
10.1021/jo015593q CCC: $20.00 © 2001 American Chemical Society Published on Web 10/10/2001
Rotational Barriers in Axially Chiral DMAPs
J. Org. Chem., Vol. 66, No. 22, 2001 7395
Figure 1. Experimentally determined barriers to rotation (∆G# (kJ/mol)) and associated kinetic parameters (∆H# (kJ/mol) and ∆S# (J mol-1 K-1)) for enantiomerization.1 Key: (a) obtained from a computer simulation of dynamic HPLC profiles; (b) values not determined, atropisomers inseparable on chiral HPLC (see text); (c) obtained from Eyring plots of racemization data;1 (d) a lower limit, the plateau between atropisomers by chiral HPLC too low to simulate.
elution profiles.9 We were unable to determine the value of ∆G# for biaryl 4 because we could not achieve good separation of its atropisomers by enantioselective HPLC.10 The kinetic parameters for enantiomerization1 of configurationally stable derivatives 5, 6, 9, and 10 were determined from Eyring plots for the racemization1 of individual enantiomers in sealed tubes in benzene in the temperature range 100-180 °C. The trend in ∆G# values along the 5-azaindoline series shows, as expected, that tri-ortho-substituted biaryls 5 and 6 have significantly higher ∆G# values than di-orthosubstituted biaryls 1-3. We expected biaryl 4 to display an intermediate value of ∆G# because, although it is triortho substituted, o-alkoxy substituents are known to be less effective at hindering biphenyl rotation than carbonbased substituents.11 However, our inability to resolve the atropisomers of this compound by enantioselective HPLC, combined with the unusual appearance of its 1H NMR spectrum10 and the knowledge that a number of biaryl systems comprising pyridyl rings display anomalously low barriers to rotation,12 encouraged us to prepare (8) The plateau between atropisomer peaks in the HPLC should be at least 10% of the height of the leading peak for simulation purposes. For biaryl 8, this was not the case within the temperature range accessible using the Chiralcel OD column (max 40 °C); hence, the value of ∆G# for this derivative is a lower limit. (9) The temperature at which ∆G# is simulated varies: 1 (20 °C), 2 (10 °C), 3 (25 °C), 7 (32 °C), and 8 (40 °C). No attempt has been made to normalize these to a common temperature. If ∆S# values for these derivatives are of magnitudes similar to those of biaryls 5 and 6, which is likely, then such a normalization (within this limited temperature range) would not alter the values by more than 1 kJ/mol. (10) Columns tried: Chiralcel OB, OD, and OJ and Chiralpak AD. Biaryl 4 displays an anomalous 1H NMR spectrum in that both pairs of methylene protons of the pyrroline ring are almost isochronous (i.e., they appear as a pair of triplets at 250 MHz, although additional complexity is discernible at 500 MHz). All the other 5-azaindoline derivatives are clearly anisochronous and show complex splitting patterns at 250 MHz (see Supporting Information for ref 3). This presumably reflects a coincidental equivalence in the magnetic environment of these diastereotopic methylenes for this particular compound. (11) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds; Wiley: New York, 1994. (12) Slany, M.; Stang, P. J. Synthesis 1996, 1019-1028 and references therein.
biaryls 2 and 3. We reasoned that if 2-methoxy-1naphthyl biaryl 4 displayed a low barrier to rotation as the result of conjugation across the biaryl bond, then so too would 4-methoxy-1-naphthyl biaryl 2, but not 3-methoxy-1-naphthyl biaryl 3.13,14 The fact that both these biaryls have almost identical values of ∆G# proves that any such conjugation is negligible but does not provide a guide to the value of ∆G# for biaryl 4. We were particularly interested in knowing whether derivatives such as biaryl 4 were configurationally stable because these are intermediates en route to derivatives such as 5 and 6, which we required for testing as chiral catalysts. Thus, preparative separation of the enantiomers of biaryl 4 could15 provide access to a wide range of such catalyst candidates in an enantiomerically pure form without the need for time-consuming resolution of each derivative individually. This was our first motivation for the computational studies described below. The second motivation was our finding that, contrary to our expectations, at ambient temperatures, the values of ∆G# for 3-aryl-DMAP6 derivatives 7-10 exceed those of the corresponding 5-azaindolines.3 Moreover, the entropies of activation for rotation (∆S#) for 5-azaindoline derivatives 5 and 6 are roughly double those of the corresponding DMAP derivatives 9 and 10. We had expected the reverse trend due to the entropic cost of restricting rotation about the CAr-N bond in DMAP derivatives in the rate-limitng TS. The third motivation for the computational studies was to delineate which interactions are important in restricting rotation in these systems. It was expected that this information would aid our design of configurationally stable catalyst candidates and also, given that biaryls invariably occupy equilibrium geometries wherein θ (the inter-ring dihedral angle) is *90°,11 aid our efforts to (13) Wolf, C.; Ko¨nig, W. A.; Roussel, C. Liebigs Ann. 1995, 781786. (14) Wolf, C.; Hochmuth, D. H.; Ko¨nig, W. A.; Roussel, C. Liebigs Ann. 1996, 357-363. (15) Provided that racemization could be prevented during subsequent manipulations.
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Figure 2. PM3-derived energy profiles for rotation about the biaryl axis in derivatives 1-10 with calculated barriers to rotation (∆G# (kJ/mol)).
elucidate the origins of stereoinduction by these catalysts in asymmetric acylation processes. The procedure used to generate PM3-optimized geometries for ground states (GSs) and TSs is described in Experimental Section and was applied to biaryls 1-10. The free energies of enantiomerization (∆G#) generated in this way correspond to the energy required to pass over the lower of the two TSs. The ∆G#PM3 values are shown in Figure 2 along with the energy profiles. The correlation between the PM3-derived ∆G# values and the experimental values across the 5-azaindoline series 1-6 is shown graphically in Figure 3. Although the absolute values are underestimated,16 the relative values are in close agreement and allow an estimate of the value of ∆G#293 for biaryl 4 as ∼128 kJ/mol (as shown in Figure 3). This corresponds to a half-life of >10 years at ambient temperature and suggests that resolution should be feasible.
The relative broadness of the maxima corrresponding to the second transition state (at θ ∼ 180°, TS2) in the 5-azaindoline series when compared to the DMAP series is due to the presence of a hydrogen bond17 between the pyramidal pyrroline nitrogen and the naphthalene perihydrogen18-20 (hydrogen bond lengths: 4, 1.83 Å; 5, 1.93 Å; 6, 1.87 Å) near this TS. The presence of a hydrogen (16) The PM3 rotational barriers were computed for 0 K. For the 5-azindoline series, they are ∼11% below the experimentally determined values. When corrected to 298 K using a scaling factor of 0.9761, the ∆G# values become (1) 89.1, (2) 92.1, (3) 90.2, (4) 114.6, (5) 123.6, and (6) 122.0 kJ/mol, respectively. Although the mean difference to experiment then becomes 6%, the scaled values are above and below the experimental values. For the scaling method, see: Scott, A. P.; Radom, L. J. Phys. Chem. 1996, 100, 16502-16513. (17) Grzybowski, B. A.; Ishchenko, A. V.; DeWitte, R. S.; Whitesides, G. M.; Shakhnovich, E. I. J. Phys. Chem. B 2000, 104, 7193-7298. (18) Afonin, A. V.; Vashchenko, A. V.; Takagi, T.; Kimura, A.; Fujiwara, H. Can. J. Chem. 1999, 77, 416-424. (19) Park, J. K. J. Phys. Chem. A 2000, 104, 5093-5100.
Rotational Barriers in Axially Chiral DMAPs
J. Org. Chem., Vol. 66, No. 22, 2001 7397 Table 1. Changes in the PM3-Derived C-H and N‚‚‚H Bond Lengths between the GS and the TS Structures of Molecules 1 (R ) H), 4 (R ) OMe), 5 (R ) Me), and 6 (R ) Ph)a
Figure 3. Correlation of experimental and PM3 values of ∆G# for 5-azaindoline derivatives 1-6, showing the predicted barrier to rotation for biaryl 4 (see text).
bond length (Å)
bond 1 (R ) H)
C7-H21 C2-H24 N17‚‚‚H24 N17‚‚‚H21
4 (R ) OMe)
C7-H21
5 (R ) Me)
C7-H21
N17‚‚‚H21
N17‚‚‚H21 6 (R ) Ph)
C7-H21 N17‚‚‚H21
GS TS2 GS TS1 TS1 TS2
1.097 1.104 1.096 1.096 2.290 1.921
GS TS2 TS2
1.097 1.112 1.830
GS TS2 TS2
1.097 1.107 1.928
GS TS2 TS2
1.097 1.110 1.873
a
A lengthening of the C7-H21 bond length and a shortening of the N17‚‚‚H21 distance between the GS and TS2 in all cases are indicative of hydrogen bond formation.
Figure 4. PM3-derived structure of TS2 for the enantiomerization of 5-azaindoline-based biaryl 5, showing the pyramidalization of the pyrroline nitrogen and its interaction with the naphthalene peri-hydrogen via a hydrogen bond (1.93 Å).
bond was verified by orbital analysis (e.g., Figure 4) and by frequency vibrations seen for these TSs using Hyperchem.21 There is a significant lengthening of the key C-H bonds between the GS and TS2 of biaryls 1 and 4-6 (Table 1). By contrast, there is no lengthening of the corresponding C-H bond between the GS and the first transition state (at θ ∼ 0°, TS1) of biaryl 1 (Table 1). For 5-azaindolines 5 and 6 (Figure 2), for which TS2 is rate limiting, this interaction accounts for the smaller values of ∆G# and ∆H# and larger values of |∆S#| observed experimentally relative to those of DMAP derivatives 9 and 10 (Figure 2). (20) Desiraju, G.; Steiner, T. The Weak Hydrogen Bond: Applications to Structural Chemistry and Biology; Oxford University Press: New York, 1999. (21) HyperChem version 5.11 for Windows molecular modelling system; Hypercube, Inc.: Waterloo, Ontario, Canada, 1999.
For the non-2-substituted naphthalene derivatives 1-3 (Figure 2) for which the barrier corresponding to TS1 is rate limiting, however, the PM3 calculations incorrectly predict that the 5-azaindoline series should be rotationally more stable than their DMAP analogues. This is probably because the PM3 calculations allow free rotation about the CAr-N bond in these latter structures. Ab initio calculations at the HF/STO-3G level on 3-(1-naphthyl)-DMAP 7 show that, in fact, conjugation between the dialkylamino nitrogen and the pyridine ring is maintained in TS1 (Figures 5 and 6). The conjugation uses the pz wave function of nitrogen and the πz ring wave function (Tables 2 and 3). Note that the angles [
